(7) Project Summary/Abstract Substance use disorder is a chronic, intractable disease characterized by pathological risk-taking behavior, which engenders ongoing drug seeking despite the risk of consequences. This proposal harnesses a rat model to understand the neuronal activity that contributes to risky decision-making. The Risky Decision-Making Task (RDT) offers choice between a small, safe reward and a large reward accompanied by an escalating risk of mild foot shock. While risk-taking on average decreases with increasing risk of punishment, the RDT reveals wide variability in risk preference, including a subpopulation of rats that consistently prefer the large reward despite high risk of punishment. Understanding the neuronal mechanisms of this natural variability in risky decision-making may contribute to development of treatments that target aberrant decision-making processes in substance abusers. A likely locus of the functional activity driving risky decision-making is the orbitofrontal cortex (OFC), an area implicated in several modalities of risk-based decision-making as well as vulnerability to substance use. Experiments in this proposal will assess how differences in OFC processing drive individual differences in risk-taking by measuring and manipulating OFC activity during risky decision-making. Aim one will utilize in vivo single-unit electrophysiology to measure functional neuronal activity in OFC during risky decision-making. Activity will be measured during a specially designed version of RDT that parses apart distinct epochs within the decision-making process: pre-decision deliberation, and post-decision outcome anticipation. To determine how OFC predicts individual biases in risk-taking, event-evoked OFC activity will be compared between rats with different levels of risk preference. Aim two will utilize optogenetic inhibition to suppress OFC activity during different epochs within risky decision-making. This will identify the causal role of OFC in driving risk-taking, and determine if OFC modulation of risk-taking diverges as a function of risk- preference. The experiments outlined above will both measure and manipulate OFC activity during an understudied form of addiction-relevant risky decision-making, which may lead to novel biomarkers and/or precise treatments for the chronic insensitivity to risk of punishment observed in addiction. In addition, this proposal will offer a strong training component including critical technical skills, complex data analysis and signal processing, the opportunity for multiple high impact publications, and strong mentorship from a team of investigators at various career stages.